Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention relates to new compounds for medicaments, which have a glycogen synthase kinase-3 beta
• glycogen synthase kinase-3 beta (GSK-3 ⁇ ), a protein kinase, is involved in the causes of various diseases as noted in the following.
• Type-II diabetes is a disease in which the insulin reactivity of pancreatic ⁇ cells becomes low and glucose in blood increases. As a result, complications such as diabetic nephropathy, retinosis, heart disease and the like are induced.
• GSK-3 ⁇ acts for inhibiting glycogen accumulation in peripheral tissues, lowering insulin response and increasing glucose in blood by phosphorylating glycogen synthase. Lithium having a GS -3 ⁇ -inhibitory activity actually lowers glucose in blood by a GSK-3 ⁇ -inhibitory activity (Proc. Nat. Acad. Sci, 93, 8455 (1996)). Therefore, medicaments having a GSK-3 ⁇ -inhibitory activity are considered to be a pharmaceutical agent effective for the improvement of Type II diabetes and complications thereof.
• GSK-3 ⁇ is involved in both the amyloid aggregation and the neurofibril changes as follows. (1) It binds with variant presenilin and increase production of insoluble amyloid (Proc. Nat. Acad. Sci., 95, 9637 (1998)). (2) It causes phosphorylation of the Tau protein, which causes neurofibril changes, and weakens the backbones of neurons to induce neuronal death (Neurosci. Lett., 128, 195 (1991)).
• Tat which is a protein produced by HIV virus that causes AIDS, enhances GSK-3 ⁇ activity in neurons to induce neuronal death (J. Neurochem., 73, 578 (1999)).
• GSK-3 ⁇ inhibitors are considered to be medicaments effective for improving neurodegenerative diseases including Alzheimer's dementia.
• Lithium and valproic acid which have anti-manic- depressive activity, have a GSK-3 ⁇ inhibitory activity (J. Neurochem., 72, 1327 (1999)).
• the relationship between anti- manic-depressive activity and GSK-3 ⁇ inhibitory activity is unclear, but a suppressive activity on glutamic acid toxicity is considered to be partly responsible for maintaining neuronal activity (Proc. Nat. Acad. Sci., 95, 2642 (1998)).
• GS -3 ⁇ inhibitors are considered to be medicaments effective for improving manic-depressive psychosis.
• NF-AT a transcription factor
• calcineurin a transcription factor
• 3 ⁇ inhibitors are considered to be medicaments effective for immunopotentiation.
• JP-A-3-272189 invention drawn to an improved synthesis method of mevalolacton intermediates
• JP- A-2-275878 therapeutic agents for hyperlipoproteinemia and atherosclerosis
• JP-A-1-272584 therapeutic agents for hyperlipoproteinemia
• JP-A-59-65089, JP-A-59-118786, JP- A-60-56979, JP-A-60-197685 and the like disclose 6-methyl-4- substituted phenyl-4,7-dihydropyrazolo[3,4-b]pyridine-5- carboxylate compounds used for the treatment of cardiovascular diseases, and they are produced by similar methods.
• the present inventors reproduced the following reaction A according to the method described in JP-A-59-65089, but failed to obtain the compound of Example 14 (formula (IV) in the following) described therein. They confirmed that only the pyrazolo[l,5-a]pyrimidine derivative represented by the formula (V) could be produced.
• An object of the present invention is to provide novel compounds having a selective and strong inhibitory activity against glycogen synthase kinase-3 beta (GSK-3 ⁇ ), and further, medicaments comprising them.
• the present inventors have intensively studied to achieve the above object, and have found that 4,7- dihydropyrazolo[ 3, 4-b] yridine derivatives have a selective and strong inhibitory activity on GSK-3 ⁇ , which resulted in the completion of the present invention.
• the present invention relates to medicaments comprising, as an active ingredient, dihydropyrazolopyridine compounds represented by the following formula (I) , which have a GSK-3 ⁇ -inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
• formula (I) dihydropyrazolopyridine compounds represented by the following formula (I) , which have a GSK-3 ⁇ -inhibitory activity and can be used as medicaments, optical isomers thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.
• R° is hydrogen, alkyl, acyl, cycloalkyl, formyl, haloalkyl, aminoalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, aminocarbonyl, alkylthiocarbonyl, carboxyalkyl, cycloalkoxyalkyl, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, acyloxyacetyl, acyloxyalkyl, phenyl optionally having substituent( s) , aromatic heterocyclic group optionally having substituent( s) , phenylalkyl optionally having substituent(s) , or a group of the formula: -COOR 8 (wherein R 8 is hydrogen, alkyl, aryl optionally having substituent(s) or aralkyl optionally having substituent(s)) ; R 1
• aromatic heterocyclic group (5) a group derived from a benzene ring fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring,
• R 6 and R 7 are each phenyl optionally having substituent( s) or an aromatic heterocyclic group, or R 2 and R 3 in conjunction form a ring optionally containing heteroatom(s) , wherein the ring may be fused with a benzene ring optionally having substituent( s) ;
• R 4 is alkoxycarbonyl, aminocarbonyl, hydrazinocarbonyl, alkylthiocarbonyl, formyl, carbamoyl, alkylthio, phenylthio, alkylsulfinyl, phenylsulfinyl, alkylsulfonyl, phenylsulfonyl, dialkylphosphinyl, dialkylphosphonyl, cyano or nitro; and
• R 5 is hydrogen, cyano, formyl, alkyl, cycloalkyl, alkoxyalkyl, phenoxyalkyl, dialkoxyalkyl, hydroxyalkyl, haloalkyl, carboxyalkyl, cycloalkoxyalk l, phenylthio, alkylsulfinyl, alkylsulfonyl, phenylsulfonyl, mercaptoalkyl, alkylthioalkyl, alkoxycarbonylalkyl, alkoxycarbonylethenyl, aryl optionally having substituent(s) (particularly phenyl), an aromatic heterocyclic group or phenylalkyl, or a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom(s) , which is fused with a benzene ring, or R 4 and R 5 in conjunction may form a 5 or 6 membered
• R 5 is alkyl having 2 to 8 carbon atoms, cycloalkyl, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, phenyl optionally having substituent( s) , an aromatic heterocyclic group or phenylalkyl, or an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
• a medicament comprising a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof.
• a pharmaceutical composition comprising a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof or a hydrate thereof, and a pharmaceutically acceptable additive.
• a glycogen synthase kinase-3 beta inhibitor comprising a compound selected from the group consisting of a dihydropyrazolopyridine compound of the above-described 1, an optically active form thereof, a pharmaceutically acceptable salt thereof and a hydrate thereof.
• Alzheimer's disease ischemic cerebrovascular disorder
• Down's syndrome cerebral ischemia due to cerebral amyloid angiopathy
• progressive supranuclear paralysis progressive supranuclear paralysis
• subacute sclerosing panencephalitic Parkinsonism postencephalitic Parkinsonism
• boxer's encephalopathy Parkinson dementia complex of Guam
• Lewy body disease Pick's
• Fig. 1 shows the GSK-3 ⁇ -inhibitory activity of the compounds of Example 47 and Example 137.
• Fig. 2 shows the effect of the compound of Example 66 on amyloid ⁇ -induced cytotoxicity.
• Fig. 3 shows the GSK-3 ⁇ -inhibitory effect of the compound of Example 27 in a gerbil brain ischemia model.
• the formula (I) indicates the presence of tautomers represented by the following formulas (I-a) and (I-b), based on the positions of hydrogen atoms of the pyrazole ring.
• the present invention encompasses each isomer of formulas (I-a) and (I-b), and a mixture of these isomers.
• Alkyl means a linear or branched carbon chain of 1 to 8 carbon atom(s), and includes methyl, ethyl, propyl, butyl, pentyl(a yl) , hexyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl and the like, with a preference for alkyl having 1 to 4 carbon atom(s).
• the alkyl of R 5 is preferably alkyl having 2 to 8 carbon atoms.
• alkyl having 2 to 8 carbon atoms concretely includes ethyl, propyl, butyl, pentyl(amyl) , hexyl, heptyl and octyl, or a structural isomer thereof, such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-butyl and the like.
• Alkyl having 2 to 4 carbon atoms is more preferable, and propyl is particularly preferable.
• Acyl includes alkylcarbonyl having 2 to 8 carbon atoms, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like, and aromatic acyl having 7 to 12 carbon atoms, such as benzoyl, naphthoyl, cinnamoyl, benzylcarbonyl and the like.
• the benzene and naphthalene rings may have 1 to 5 substituent( s) .
• Cycloalkyl means a cyclic carbon chain of 3 to 8 carbon atoms.
• Cycloalkyl concretely includes, for example, cyclopropyl, eyelobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, with a preference for cycloalkyl having 3 to 6 carbon atoms.
• Halogen represents fluorine, chlorine, bromine or iodine.
• Amino is primary amino, or secondary or tertiary amino having the above alkyl, and includes, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropylamino, butylamino, dibutylamino and the like, with a preference for tertiary amino containing alkyl having 1 to 4 carbon atom(s).
• Alkylthio is a linear or branched alkylthio having 1 to 6 carbon atom(s), and includes, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio(amylthio) , hexylthio and structural isomers thereof, such as isopropylthio, isobutylthio, sec-butylthio, tert-butylthio, isopentylthio, neopentylthio, tert-pentylthio and the like, with a preference for alkylthio having 1 to 3 carbon atom(s).
• Haloalkyl is the above alkyl substituted by 1 to 5 halogen(s), and represents fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2, 2,2-trifluoroethyl, 2,2,3,3,3-pentafluoropropyl and the like.
• Aminoalkyl is the above-mentioned alkyl having the above amino, and includes, for example, aminomethyl, methylaminomethyl, dimethylaminomethyl, 2-aminoethyl, 2- methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl, 2- diethylaminoethyl and the like, with a preference for aminoalkyl containing alkyl having 1 to 4 carbon atom(s) having tertiary amino.
• Acylamino is acylamino having the above acyl, and represents, for example, acetylamino, propion lamino, butyrylamino, valerylamino, pivaloylamino, benzoyla ino, phenyla ⁇ etylamino, phenylpropionylamino, phenylbutyrylamino and the like.
• Alkoxy is alkoxy having the above alkyl, and includes, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy(amyloxy) , hexyloxy and structural isomers thereof, such as isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentyloxy, neopentyloxy, ter -pentyloxy and the like, with a preference for alkoxy having 1 to 4 carbon atom(s).
• Cycloalkoxy is alkoxy having the above cycloalkyl, and includes, for example, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like, with a preference for cycloalkoxy having cycloalkyl having 3 to 6 carbon atoms.
• Phenylalkoxy is phenylalkoxy having the above alkoxy, and includes, for example, benzyloxy, 1-phenylethoxy, 2- phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-methyl-l- phenylethoxy, l-methyl-2-phenylethoxy, 1-phenylpropoxy, 2- pheylpropoxy, 1-methyl-1-phenylpropoxy, l-methyl-2- phenylpropoxy, 1-methyl-3-phenylpropoxy and the like, with a preference for phenylalkoxy containing alkoxy having 1 to 4 carbon atom(s) .
• aminoalkoxy is aminoalkoxy consisting of the above alkoxy and amino, and includes, for example, aminomethoxy, methylaminomethoxy, dimethylaminomethoxy, 2- di ethylaminoethoxy, 3-dimethylaminopropoxy, 4- dimethylaminobutoxy and the like, with a preference for aminoalkoxy consisting of tertiary amino containing alkyl having 1 to 4 carbon atom(s), and alkoxy having 1 to 4 carbon atom(s) .
• Alkoxyalkyl is alkoxyalkyl consisting of the above alkoxy and alkyl, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxyethyl, propoxymethyl, isopropoxymethyl and the like, with a preference for alkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s).
• Phenoxyalkyl is phenoxyalkyl containing the above alkyl, and includes, for example, phenoxy ethyl, 2- phenoxyethyl, 3-phenoxypropyl and the like, with a preference for phenoxyalkyl containing alkyl having 1 to 4 carbon atom(s) .
• Dialkoxyalkyl is dialkoxyalkyl consisting of the above alkyl and alkoxy, and includes, for example, dimethoxymethy1, diethoxymethy1, 2, 2-dimethoxyethyl, 2,2-diethoxyethyl and the like, with a preference for dialkoxyalkyl consisting of alkoxy having 1 to 4 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
• Hydroalkyl is hydroxyalkyl having the above alkyl, and includes, for example, hydroxymethyl, 2-hydroxyethyl, 3- hydroxypropyl and the like, with a preference for hydroxylalkyl containing alkyl having 1 to 4 carbon atom(s).
• Alkoxycarbonyl is alkoxycarbonyl having the above alkoxy, and includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and structural isomers thereof, such as isopropoxycarbonyl, isobutoxycarbonyl, see- butoxycarbonyl, tert-butoxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl and the like, with a preference for alkoxycarbonyl, in which the alkoxy moiety has 1 to 4 carbon atom(s). However, R 4 is preferably alkoxycarbonyl having 2 to 5 carbon atoms.
• Aminocarbonyl is aminocarbonyl having the above amino, and includes, for example, aminocarbonyl (carbamoyl), methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, propylaminocarbonyl, dipropylaminocarbonyl, phenylcarbamoyl, benzylcarbamoyl and the like, with a preference for tertiary-aminocarbonyl containing alkyl having 1 to 4 carbon atom(s).
• Alkylthiocarbonyl is alkylthiocarbonyl having the above alkylthio, and includes, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl and structural isomers thereof, such as isopropylthiocarbonyl, isobutylthiocarbonyl, sec-butylthiocarbonyl, tert- butylthiocarbonyl and the like, with a preference for alkylthiocarbonyl, in which the alkyl moiety has 1 to 3 carbon atoms .
• Carboxyalkyl is carboxyalkyl having the above alkyl, and includes, for example, carboxymethyl, carboxyethyl, carboxypropyl and the like, with a preference for carboxyalkyl containing alkyl having 1 to 4 carbon atom(s).
• Cycloalkoxyalkyl is cycloalkoxyalkyl having the above cycloalkoxy and alkyl, and includes, for example, cyclopropoxymethyl, cyclopropoxyethyl, cyclobutoxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl and the like, with a preference for cycloalkoxyalkyl consisting of cycloalkoxy having 3 to 6 carbon atoms and alkyl having 1 to 4 carbon atom(s) .
• Alkylsulfinyl is alkylsulfinyl having the above alkyl, and includes, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl and the like, with a preference for alkylsulfinyl containing alkyl having 1 to 4 carbon atom(s).
• Alkylsulfonyl is alkylsulfonyl having the above alkyl, and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and the like, with a preference for alkylsulfonyl containing alkyl having 1 to 4 carbon atom(s) .
• Mercaptoalkyl is mercaptoalkyl having the above alkyl, and includes, for example, mercaptomethyl, mercaptoethyl, mercaptopropyl and the like, with a preference for mercaptoalkyl containing alkyl having 1 to 4 carbon atom(s).
• Alkylthioalkyl is alkylthioalkyl having the above alkylthio and alkyl, and includes, for example, methylthiomethy1, methylthioethyl, methylthiopropy1, ethylthiomethyl, ethylthioethyl, ethylthiopropyl and the like, with a preference for alkylthioalkyl consisting of alkylthio having 1 to 3 carbon atom(s) and alkyl having 1 to 4 carbon atom(s) .
• Aryl is aryl having 6 to 14 carbon atoms, and includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and the like. They may have 1 to 5 substituent( s) and substitution sites are not particularly limited.
• Alkyl is aralkyl wherein the above alkyl is substituted by the above aryl, and includes benzyl, 2- phenylethyl, 3-phenylpropyl, 1-naphthylmethyl, 2- naphthylmethyl and the like. These may have 1 to 5 substituent( s) on the aryl moiety.
• Acyloxyacetyl is acyloxyacetyl having the above acyl, and includes, for example, acetyloxyacetyl, propionyloxyacetyl, butyryloxyacetyl, benzoyloxya ⁇ etyl and the like.
• “Acyloxyalkyl” is acyloxyalkyl having the above acyl and alkyl, and includes, for example, acetyloxymethyl, propionyloxymethyl, butyryloxymethyl, benzoyloxymethyl, 2- acetyloxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2- benzoyloxyethyl and the like.
• Aromatic heterocyclic group is a 5- or 6-membered aromatic heterocyclic ring optionally containing 1 to 3 heteroatom( s) of nitrogen atom, oxygen atom and sulfur atom, and includes, for example, thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyridazine, pyrimidine, pyrazine and the like.
• the substituent of the "aromatic heterocyclic ring optionally having substituent( s) " is exemplified by those mentioned for the "substituent” below, wherein the number of the substituent is generally 1 to 5, preferably 3.
• Phenylalkyl is phenylalkyl having the above alkyl, and includes, for example, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-phenylethyl, l-methyl-2-phenylethyl, 1- phenylpropyl, 2-phenylpropyl, 1-methy1-1-phenylpropyl, 1- methyl-2-phenylpropyl, l-methyl-3-phenylpropyl and the like, with a preference for phenylalkyl consisting of phenyl and alkyl having 1 to 4 carbon atom(s).
• Alkoxycarbonylalkyl is alkoxycarbonylalkyl having the above alkoxycarbonyl and alkyl, and includes, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3- ethoxycarbonylpropyl and the like.
• Alkoxycarbonylethenyl is alkoxycarbonylethenyl having the above alkoxycarbonyl, and includes, for example, 2- methoxycarbonylethenyl, 2-ethoxycarbonylethenyl, 2- butoxycarbonylethenyl, 2-tert-butoxycarbonylethenyl and the like.
• Dialkylphosphinyl is dialkylphosphinyl having the above alkyl, and includes, for example, dimethylphosphinyl, diethylphosphinyl, dipropylphosphinyl and the like, with a preference for dialkylphosphinyl containing alkyl having 1 to 4 carbon atom(s).
• Dialkylphosphonyl is dialkylphosphonyl having the above alkyl, and includes, for example, dimethylphosphonyl, diethylphosphonyl, dipropylphosphonyl and the like, with a preference for dialkylphosphonyl containing alkyl having 1 to 4 carbon atom(s).
• substituted includes alkyl, acyl, cycloalkyl, phenyl, aromatic heterocyclic ring, phenylalkyl, hydroxy, thiol, halogen, amino, formyl, carbamoyl, cyano, nitro, alkylthio, haloalkyl, aminoalkyl, acylamino, alkoxy, cycloalkoxy, phenoxy, phenylalkoxy, aminoalkoxy, alkoxyalkyl, phenoxyalkyl, hydroxyalkyl, alkoxycarbonyl, alkylsulfinyl, aminocarbonyl, alkylthiocarbonyl and the like.
• Ring optionally containing heteroatom(s) is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom(s) consisting of nitrogen atom, oxygen atom and sulfur atom, with particular preference given to a ring containing sulfur atom.
• the ring may be substituted by one or more of the above substituents or oxo groups.
• the substitution site is not particularly limited.
• This ring is formed by R and R in the formula (I) together with the attached carbon atom. By forming this ring, a spiro ring is formed in the compound of the formula (I) .
• the above ring can be fused with a benzene ring optionally having substituent( s) .
• Such a ring includes, for example, 2,3-dihydrobenzo[b]thiophene, 2,3- dihydrobenzo[b]thiophen-l-oxide and the like.
• a group derived from a benzene ring, which is fused with a saturated or unsaturated 5 or 6 membered carbocyclic ring represents a group derived from naphthalene, 1,2- dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, indan and the like, with preference given to naphthalene (namely naphthyl) and particular preference given to 1-naphthyl.
• a group derived from a benzene ring fused with a saturated or unsaturated 5 to 7 membered carbocyclic ring containing 1 to 3 heteroatom( s) includes the following groups and the like.
• 2 ,1 ,3-benzoxadiazole and 3 ,4-dihydro-2H- benzopyrane are preferable, and 2 ,1 ,3-benzoxadiazol-4-yl and 3 ,4-dihydro-2H-benzopyran-8-yl are particularly preferable.
• a group derived from a 5 to 7 membered saturated or unsaturated carbocyclic ring containing 1 to 3 heteroatom (s) , which is fused with a benzene ring includes the following groups and the like.
• the "5 or ⁇ -membered ring optionally containing heteroatom (s) " is a 5 or 6 membered carbocyclic ring optionally containing 1 to 3 heteroatom (s) consisting of nitrogen atom, oxygen atom and sulfur atom.
• heteroatom s
• Examples thereof include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, furazan, pyran, pyridine, pyridazine, pyrimidine, pyrazine, pyrroline, pyrrolidine, imidazoline and imidazolidine.
• furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, furazan and pyridine are preferable.
• the compounds, represented by the formula (I) of the present invention can be converted to acid addition salts with pharmaceutically acceptable acids and such acid addition salts are also encompassed in the present invention.
• acid addition salts include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, glutamic acid and the like.
• the compounds of the present invention can form hydrates, solvates with ethanol and the like, and crystal polymorphs.
• optical isomers and racemates thereof can be present, and all of these are encompassed in the present invention.
• a compound wherein R° is hydrogen can be synthesized as shown in the following according to the method described in J. Chem. Soc, Perkin Trans. 1, 947 (1996) and the like. (First Production Method)
• R 2 , R 3 , R 4 and R 5 are as defined above.
• Meldrum's acid of the formula (VI) and a carbonyl derivative of the formula (VII) are reacted with a carbonyl derivative of the formula (VIII) to give an amide derivative of the formula (IX).
• the reaction is carried out in the presence of a carboxylic acid solvent inert to the reaction.
• a carboxylic acid solvent inert to the reaction.
• the solvent formic acid, acetic acid, propionic acid, butyric acid, valeric acid and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
• the obtained amide derivative of the formula (IX) is reacted in the presence of dimethylformamide and phosphorus oxychloride to give a formyl derivative of the formula (X) .
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethyIformamide, dimethyl sulfoxide and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
• the compound (I) of the present invention can be produced by reacting the obtained formyl derivative of the formula (X) in the presence of hydrazine.
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent inert As the solvent, ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, pyridine, alcohol and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
• the carbonyl derivative of the formula (VII), which is a starting material, can be synthesized according to the methods described in J. Org. Chem., 46, 783 (1981), Eur. J. Med. Chem., 31, 3 (1996) and Tetrahedron Lett., 24, 5023 (1983).
• the carbonyl derivative of the formula (VIII) can be synthesized according to the method described in Synthesis, 290 (1993). (Second Production Method)
• R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.
• the compounds (I) of the present invention can be produced by reacting aminopyrazole of the formula (XI) and a carbonyl derivative of the formula (VII) with a carbonyl derivative of the formula (VIII).
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent inert to the reaction.
• ether, tetrahydrofuran, dioxane, ethyl acetate, acetonitrile, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethyl sulfoxide, alcohol and the like are generally used.
• the reaction is carried out at any temperature, for example, from 0°C to 200°C, preferably from 60°C to 100°C.
• a compound wherein R° is a substituent other than hydrogen can be synthesized as follows. (Third Production Method)
• R°, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, and X represents halogen, provided that R° is not hydrogen.
• the compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with halide of the formula (XII) in the presence of a base.
• a base includes, for example, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and the like.
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone and the like.
• the reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
• R°, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above, provided that R° is not hydrogen.
• the compounds (I) of the present invention can be produced by reacting a dihydropyrazolopyridine derivative of the formula (XI) with anhydride of the formula (XIII) in the presence of a base.
• a base includes, for example, triethyla ine, pyridine, 4-dimethylaminopyridine and the like.
• the reaction is carried out in the presence of a solvent inert to the reaction.
• a solvent one without hydroxy group is generally used, such as tetrahydrofuran, ethyl acetate, benzene, toluene, chloroform, dichloromethane, dimethylformamide, dimethylimidazolidinone, pyridine and the like.
• the reaction is carried out at any temperature, for example, from -10°C to 200°C, preferably from 0°C to 100°C.
• the compound (I) of the present invention thus produced can be isolated and purified as a free compound or a salt thereof. Isolation and purification is carried out by a conventional chemical process such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various kinds of chromatography and the like. When the purified product obtained is a racemate, a desired optically active compound can be separated by, for example, fractional recrystallization with optically active acid, or passing through a column packed with optically active carrier.
• the present invention also encompasses optically active compounds.
• the compounds of the present invention obtained by the above methods have a weak inhibitory activity on kinases other than GSK-3 ⁇ such as CaM kinase II, MAP kinase, Casein kinase, PKA, PKC and ROCK, but have a strong inhibitory activity on GSK-3 ⁇ .
• the compounds of the present invention have a GSK-3 ⁇ -selective inhibitory activity and can be medicaments with small side-effect for diabetes, diabetic complications and neurodegenerative diseases (Alzheimer's disease, ischemic cerebrovascular disorders, Down's syndrome, cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, boxer's encephalopathy, Parkinsonism dementia complex of Guam, Lewy body disease, Pick's disease, corticobasal degeneration, frontotemporal dementia, AIDS encephalopathy, Huntington's disease, manic- depressive psychosis and the like) .
• Alzheimer's disease ischemic cerebrovascular disorders
• Down's syndrome cerebral ischemia due to cerebral amyloid angiopathy, progressive supranuclear paralysis, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism,
• Formulations comprising the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives conventionally used for formulation.
• the carrier and excipient for formulation may be a solid or liquid, and include, for example, lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cacao butter, ethylene glycol and other conventionally used substances.
• Administration may be oral administration of tablet, pill, capsule, granule, powder, solution and the like, or parenteral administration of injection (intravenous injection, intramuscular injection and the like), suppository, transdermal agent and the like.
• the dose is appropriately determined on each case in consideration of symptom, age and sex of the administration subject, and the like, it is generally 1 - 1,000 mg, preferably 50 - 200 mg per day for an adult person, which is orally administered once to several times a day, or 1 - 500 mg per day for an adult person, which is intravenously administered once to several times a day, or continuously administered intravenously for 1 to 24 hours a day.
• solid compositions for oral administration tablet, powder, granule and the like are used.
• one or more active substances are mixed with at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid and magnesium aluminate.
• the composition may contain, according to a conventional method, inert additives other than diluent, for example, a lubricant such as magnesium stearate, a disintegrator such as cellulose and calcium glycolate, a stabilizer such as lactose and a solubilizer such as glutamic acid and aspartic acid.
• Tablet and pill may be coated with a gastric or enteric coating film of, for example, sucrose, gelatin, hydroxypropylcellulose and the like.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir and the like, and contain an inert diluent generally used, such as purified water and ethanol. This composition may contain an adjuvant such as wetting agent and suspending agent, a sweetener, a flavor, an aromatic and an antiseptic, in addition to the inert diluent.
• Injections for parenteral administration contain sterile aqueous or non-aqueous solution, suspension and emulsion.
• the aqueous solution and suspension include, for example, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 and the like.
• a composition may contain adjuvants such as antiseptic, wetting agent, emulsifier, dispersant, stabilizer and solubilizer. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of an antimicrobial agent, irradiation of ultraviolet ray and the like.
• a sterile solid composition may be prepared and used upon dissolution in sterile water or sterile solvent for injection prior to use.
• Example 1 The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples .
• Example 1 The present invention is described in detail in the following, based on Examples, Formulation Examples and Experimental Examples. The scope of the present invention is not limited to these examples .
• the title compound was prepared from 2- methoxybenzaldehyde , 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
• the title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 1.
• IR(KBr) :v 3277, 3209, 3094, 1668, 1593, 1514, 1313, 1213,1153, 1097, 765cm _1 .
• the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and methyl acetoacetate in the same manner as in Example 1.
• the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and t-butyl acetoacetate in the same manner as in Example 1.
• the title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and isopropyl acetoacetate in the same manner as in Example 1. MP:218-220°C.
• the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and benzyl acetoacetate in the same manner as in Example 1. MP:234°C.
• the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and N,N-dimethylacetamide in the same manner as in Example 1. MP:229°C.
• IR(KBr):v 3375, 3175, 3067, 1707, 1606, 1533, 1278, 1206, 1197, 1167cm -1 .
• the title compound was prepared from 2- fluorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
• IR(KBr):v 3290, 3178, 3069, 1703, 1608, 1537, 1280, 1232, 1174, 1138,
• the title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
• IR(KBr) :v 3321, 3178, 3070, 1703, 1610, 1535, 1278, 1224, 1184, 1145cm "1 .
• IR(KBr):v 3263,3194,3080, 1668, 1591, 1520, 1286, 1232, 1149, 1095, 1062cm -1 .
• the title compound was prepared from thiophene-2- aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
• the title compound was prepared from naphthalene-1- aldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1. MP:119-120°C.
• IR(KBr):v 3263, 3209, 3194, 3080, 1668, 1591, 1520, 1286, 1232, 1149, 106 2,750cm -1 .
• the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and methyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- met ylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- propoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- isopropyloxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- butoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- benzyloxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:128°C.
• the title compound was prepared from 2,3- difluorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2, 3- dichlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 3-fluoro-2- methylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2,3- dimethoxybenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2-chloro-3- trifluoromethylbenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25. MP:236-238°C.
• the title compound was prepared from 2-chloro-4- fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2,5- difluorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2,5- diehlorobenzaldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 5-fluoro-2- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2-chloro-5- methoxybenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:182°C.
• the title compound was prepared from pyridine-3-aldehyde and ethyl 3-ketohexanoate in the same manner as in Example 39.
• the title compound was prepared from furan-3-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:121-123°C.
• the title compound was prepared from thiophene-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:129-131°C.
• the title compound was prepared from 5-chlorothiophene- 2-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from thiophene-3- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from naphthalene-1- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25. MP:182°C.
• the title compound was prepared from naphthalene-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 1, 3-benzdioxazole- 4-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2, 3-dihydro-l, 4- benzodioxin-6-aldehyde, 3-aminopyrazole and ethyl 3- ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from benzo[b]furan-2- aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2- chlorobenzaldehyde, 3-aminopyrazole and ethyl (thiophen-2- carbonyl) acetate in the same manner as in Example 1.
• the title compound was prepared from 2- propylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
• the title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl acetoacetate in the same manner as in Example 25. MP:228°C.
• the title compound was prepared from 2,1,3- benzoxadiazole-4-aldehyde, 3-aminopyrazole and ethyl benzoylacetate in the same manner as in Example 1.

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